LncRNA SNHG11 facilitates tumor metastasis by interacting with and stabilizing HIF-1α

AbstractEpigenetic alteration is one of the hallmarks of colorectal cancer (CRC). Many driver genes are regulated by DNA methylation in CRC. However, the role of DNA methylation regulating lncRNAs remain elusive. Here, we identify that SNHG11 (small nucleolar RNA host gene 11) is upregulated by promotor hypomethylation in CRC and is associated with poor prognosis in CRC patients. SNHG11 can promote CRC cell migration and metastasis under hypoxia. Interestingly, the DNA-binding motif of SNHG11 is similar to that of HIF-1α. In addition, SNHG11-associated genes are enriched with members of the HIF-1 signaling pathway in CRC. Mechanistically, SNHG11 binds to the pVHLrecognition sites on HIF-1α, thus blocking the interaction of pVHL with HIF-1α and preventing its ubiquitination and degradation. Moreover, SNHG11 upregulates the expression of HIF-1α target genes, i.e., AK4, ENO1, HK2, and Twist1. Notably, SNHG11 can bind to the HRE sites in the promoter of these genes and increase their transcription. In summary, these results identify a SNHG11/ HIF-1α axis that plays a pivotal role in tumor invasion and metastasis.

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The HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling

Nature Communications ◽

10.1038/s41467-021-24631-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Eui Jung Moon ◽

Stephano S. Mello ◽

Caiyun G. Li ◽

Jen-Tsan Chi ◽

Kaushik Thakkar ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Invasion ◽

Critical Role ◽

Metastatic Breast ◽

Breast Cancer Patients ◽

Invasion And Metastasis ◽

Stat3 Signaling ◽

Inducible Genes ◽

Transcriptional Target

AbstractHypoxia plays a critical role in tumor progression including invasion and metastasis. To determine critical genes regulated by hypoxia that promote invasion and metastasis, we screen fifty hypoxia inducible genes for their effects on invasion. In this study, we identify v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (MAFF) as a potent regulator of tumor invasion without affecting cell viability. MAFF expression is elevated in metastatic breast cancer patients and is specifically correlated with hypoxic tumors. Combined ChIP- and RNA-sequencing identifies IL11 as a direct transcriptional target of the heterodimer between MAFF and BACH1, which leads to activation of STAT3 signaling. Inhibition of IL11 results in similar levels of metastatic suppression as inhibition of MAFF. This study demonstrates the oncogenic role of MAFF as an activator of the IL11/STAT3 pathways in breast cancer.

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The multiple myeloma–associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity

Blood ◽

10.1182/blood-2007-05-088674 ◽

2008 ◽

Vol 111 (2) ◽

pp. 856-864 ◽

Cited By ~ 102

Author(s):

Josh Lauring ◽

Abde M. Abukhdeir ◽

Hiroyuki Konishi ◽

Joseph P. Garay ◽

John P. Gustin ◽

...

Keyword(s):

Multiple Myeloma ◽

Poor Prognosis ◽

Target Genes ◽

Hematologic Malignancy ◽

Growth Factor Receptor ◽

Cellular Adhesion ◽

Tumor Formation ◽

Set Domain ◽

Cycle Arrest

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by recurrent chromosomal translocations. Patients with t(4;14)(p16;q32) are the worst prognostic subgroup in MM, although the basis for this poor prognosis is unknown. The t(4;14) is unusual in that it involves 2 potential target genes: fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET). MMSET is universally overexpressed in t(4;14) MM, whereas FGFR3 expression is lost in one-third of cases. Nonetheless, the role of MMSET in t(4;14) MM has remained unclear. Here we demonstrate a role for MMSET in t(4;14) MM cells. Down-regulation of MMSET expression in MM cell lines by RNA interference and by selective disruption of the translocated MMSET allele using gene targeting dramatically reduced colony formation in methylcellulose but had only modest effects in liquid culture. In addition, MMSET knockdown led to cell-cycle arrest of adherent MM cells and reduced the ability of MM cells to adhere to extracellular matrix. Finally, MMSET knockdown and knockout reduced tumor formation by MM xenografts. These results provide the first direct evidence that MMSET plays a significant role in t(4;14) MM and suggest that therapies targeting this gene could impact this particular subset of poor-prognosis patients.

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Transcriptional Regulation of Genes by Ikaros Tumor Suppressor in Acute Lymphoblastic Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms21041377 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1377

Author(s):

Pavan Kumar Dhanyamraju ◽

Soumya Iyer ◽

Gayle Smink ◽

Yevgeniya Bamme ◽

Preeti Bhadauria ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Tumor Suppressor ◽

Chromatin Remodeling ◽

Target Genes ◽

Cellular Proliferation ◽

Lymphoblastic Leukemia ◽

Regulatory Elements ◽

Binding Motif ◽

Functional Inactivation

Regulation of oncogenic gene expression by transcription factors that function as tumor suppressors is one of the major mechanisms that regulate leukemogenesis. Understanding this complex process is essential for explaining the pathogenesis of leukemia as well as developing targeted therapies. Here, we provide an overview of the role of Ikaros tumor suppressor and its role in regulation of gene transcription in acute leukemia. Ikaros (IKZF1) is a DNA-binding protein that functions as a master regulator of hematopoiesis and the immune system, as well as a tumor suppressor in acute lymphoblastic leukemia (ALL). Genetic alteration or functional inactivation of Ikaros results in the development of high-risk leukemia. Ikaros binds to the specific consensus binding motif at upstream regulatory elements of its target genes, recruits chromatin-remodeling complexes and activates or represses transcription via chromatin remodeling. Over the last twenty years, a large number of Ikaros target genes have been identified, and the role of Ikaros in the regulation of their expression provided insight into the mechanisms of Ikaros tumor suppressor function in leukemia. Here we summarize the role of Ikaros in the regulation of the expression of the genes whose function is critical for cellular proliferation, development, and progression of acute lymphoblastic leukemia.

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Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells

Oncogene ◽

10.1038/s41388-019-1053-6 ◽

2019 ◽

Vol 39 (6) ◽

pp. 1185-1197 ◽

Cited By ~ 5

Author(s):

Mónica López-Guerra ◽

Sílvia Xargay-Torrent ◽

Patricia Fuentes ◽

Jocabed Roldán ◽

Blanca González-Farré ◽

...

Keyword(s):

Cell Proliferation ◽

Notch Signaling ◽

Poor Prognosis ◽

Therapeutic Strategy ◽

Target Genes ◽

Notch Signaling Pathway ◽

Lymphocytic Leukemia ◽

Therapeutic Targeting ◽

Notch Ligand

Abstract Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), particularly in NOTCH1-mutated patients. We provide first evidence that the Notch ligand DLL4 is a potent stimulator of Notch signaling in NOTCH1-mutated CLL cells while increases cell proliferation. Importantly, DLL4 is expressed in histiocytes from the lymph node, both in NOTCH1-mutated and -unmutated cases. We also show that the DLL4-induced activation of the Notch signaling pathway can be efficiently blocked with the specific anti-Notch1 antibody OMP-52M51. Accordingly, OMP-52M51 also reverses Notch-induced MYC, CCND1, and NPM1 gene expression as well as cell proliferation in NOTCH1-mutated CLL cells. In addition, DLL4 stimulation triggers the expression of protumor target genes, such as CXCR4, NRARP, and VEGFA, together with an increase in cell migration and angiogenesis. All these events can be antagonized by OMP-52M51. Collectively, our results emphasize the role of DLL4 stimulation in NOTCH1-mutated CLL and confirm the specific therapeutic targeting of Notch1 as a promising approach for this group of poor prognosis CLL patients.

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A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1913307116 ◽

2019 ◽

Vol 116 (48) ◽

pp. 24184-24195 ◽

Cited By ~ 6

Author(s):

Iacovos P. Michael ◽

Sadegh Saghafinia ◽

Douglas Hanahan

Keyword(s):

Tumor Growth ◽

Target Genes ◽

Genetically Engineered ◽

Malignant Progression ◽

Metastasis Suppressor ◽

Invasion And Metastasis ◽

Biologically Relevant ◽

Genetically Engineered Mouse Model ◽

Functional Involvement

MicroRNA-mediated gene regulation has been implicated in various diseases, including cancer. This study examined the role of microRNAs (miRNAs) during tumorigenesis and malignant progression of pancreatic neuroendocrine tumors (PanNETs) in a genetically engineered mouse model. Previously, a set of miRNAs was observed to be specifically up-regulated in a highly invasive and metastatic subtype of mouse and human PanNET. Using functional assays, we now implicate different miRNAs in distinct phenotypes: miR-137 stimulates tumor growth and local invasion, whereas the miR-23b cluster enables metastasis. An algorithm, Bio-miRTa, has been developed to facilitate the identification of biologically relevant miRNA target genes and applied to these miRNAs. We show that a top-ranked miR-137 candidate gene, Sorl1, has a tumor suppressor function in primary PanNETs. Among the top targets for the miR-23b cluster, Acvr1c/ALK7 has recently been described to be a metastasis suppressor, and we establish herein that it is down-regulated by the miR-23b cluster, which is crucial for its prometastatic activity. Two other miR-23b targets, Robo2 and P2ry1, also have demonstrable antimetastatic effects. Finally, we have used the Bio-miRTa algorithm in reverse to identify candidate miRNAs that might regulate activin B, the principal ligand for ALK7, identifying thereby a third family of miRNAs—miRNA-130/301—that is congruently up-regulated concomitant with down-regulation of activin B during tumorigenesis, suggestive of functional involvement in evasion of the proapoptotic barrier. Thus, dynamic up-regulation of miRNAs during multistep tumorigenesis and malignant progression serves to down-regulate distinctive suppressor mechanisms of tumor growth, invasion, and metastasis.

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Role of Matrix Metalloproteinases in Tumor Invasion and Metastasis

Cancer Metastasis ◽

10.1017/cbo9780511976117.018 ◽

2012 ◽

pp. 183-190

Author(s):

Barbara Fingleton

Keyword(s):

Matrix Metalloproteinases ◽

Tumor Invasion ◽

Invasion And Metastasis

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Maternal Exposure to High-Fat Diet Induces Long-Term Derepressive Chromatin Marks in the Heart

Nutrients ◽

10.3390/nu12010181 ◽

2020 ◽

Vol 12 (1) ◽

pp. 181 ◽

Cited By ~ 1

Author(s):

Guillaume Blin ◽

Marjorie Liand ◽

Claire Mauduit ◽

Hassib Chehade ◽

Mohamed Benahmed ◽

...

Keyword(s):

Dna Methylation ◽

Heart Development ◽

High Fat Diet ◽

Target Genes ◽

Critical Role ◽

Maternal Exposure ◽

High Fat ◽

Cardiac Alterations

Heart diseases are a leading cause of death. While the link between early exposure to nutritional excess and heart disease risk is clear, the molecular mechanisms involved are poorly understood. In the developmental programming field, increasing evidence is pointing out the critical role of epigenetic mechanisms. Among them, polycomb repressive complex 2 (PRC2) and DNA methylation play a critical role in heart development and pathogenesis. In this context, we aimed at evaluating the role of these epigenetic marks in the long-term cardiac alterations induced by early dietary challenge. Using a model of rats exposed to maternal high-fat diet during gestation and lactation, we evaluated cardiac alterations at adulthood. Expression levels of PRC2 components, its histone marks di- and trimethylated histone H3 (H3K27me2/3), associated histone mark (ubiquitinated histone H2A, H2AK119ub1) and target genes were measured by Western blot. Global DNA methylation level and DNA methyl transferase 3B (DNMT3B) protein levels were measured. Maternal high-fat diet decreased H3K27me3, H2Ak119ub1 and DNA methylation levels, down-regulated the enhancer of zeste homolog 2 (EZH2), and DNMT3B expression. The levels of the target genes, isl lim homeobox 1 (Isl1), six homeobox 1 (Six1) and mads box transcription enhancer factor 2, polypeptide C (Mef2c), involved in cardiac pathogenesis were up regulated. Overall, our data suggest that the programming of cardiac alterations by maternal exposure to high-fat diet involves the derepression of pro-fibrotic and pro-hypertrophic genes through the induction of EZH2 and DNMT3B deficiency.

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